Dendritic spines are essential structures in brain synaptic connectivity and plasticity, and spine defects are associated with a host of neurodevelopmental and neuropsychiatric disorders. However, we know relatively little about the basic biology of how spines form, are maintained over time, and are altered during plasticity. The discovery and characterization of new molecules regulating fundamental aspects of spine biology may open entirely new avenues of research into how spine defects arise in neurological disorders. We recently made the key discovery that excitatory synaptic contacts onto a subset of C. elegans GABAergic neurons occur at spine-like protrusions from the dendrite, enabling for the first time unbiased genetic analysis of spine development and plasticity in this genetically tractable system. In this proposal we aim to discover new regulators of spines using a novel and high throughput unbiased forward genetic screening approach recently developed in an exciting collaborative effort between the Francis and Bnard labs. This approach allows us to assay spine morphology, number, and plasticity with unprecedented single dendrite and even single spine resolution in vivo. Newly identified genes in the regulation of spines will then be characterized using an array of new tools we have developed and optimized, and we will determine precise cell biological mechanisms underlying spine plasticity in vivo. Given that spine defects are strongly associated with neurodevelopmental and neuropsychiatric disorders, it is likely that a number of these genes will have causal and/or accessory roles in these diseases. This effort represents (to the best of our knowledge) the first high-throughput forward genetic screen for molecules required for spine development and maintenance in vivo. Thus, a wealth of novel regulators of spine biology, which have potential roles in neurological disease, are likely to be revealed.